Organic products containing reactive thiol functions, one method for preparing same, and biomaterials containing said products

ABSTRACT

The present invention relates to novel organic products resulting, for example, from the condensation of a dicarboxylic acid with a sulfur-containing amino acid or one of its derivatives. These products contain reactive thiol SH functions which can be oxidized to form disulfide bridges, resulting in polymers, which may or may not be crosslinked. 
     These novel organic products correspond to the following formula: ##STR1## The invention also relates to the polymers and/or networks deriving from the products of formula (I) and to one of the methods for obtaining these products and their derivatives. 
     Applications as biomaterials: sutures, ligatures, prostheses, adhesives or systems for the controlled release of active principles.

TECHNICAL FIELD

The present invention relates to novel organic products resulting, forexample, from the condensation of a dicarboxylic acid with asulfur-containing amino acid or one of its derivatives. These productscontain reactive thiol SH functions which can be oxidized to formdisulfide bridges, resulting in polymers, which may or may not becrosslinked.

PRIOR ART

One of the applications targeted by the invention is the employment ofthese novel organic products and/or of these optionally crosslinkedpolymers as biomaterials. These products could, for example, be used asstarting materials for the preparation of systems for the controlledrelease of active principles, of biological adhesives, of sutures, ofligatures, of surgical prostheses or other exogenous structures capableof substituting, at least partially, for the functions, in particularphysical or mechanical, of organs and tissues.

Synthetic biodegradable oligomers and polymers are already known whichare composed, very often, of simple and hydrolysable chains (esters oramides) of compounds capable of forming metabolites.

Thus, Patent Application EP 0,332,530 describes hydrophilic polymers,with a degree of polymerization of less than 1 000 and preferably ofbetween 20 and 300, composed of polyamides resulting from thecondensation of citric acid with diamines, such as lysine, cystamine orcystinc.

The synthesis of these polyamides presents real difficulties related tothe protection and then to the deprotection of the citric acid.

These biodegradable polyamides can be used for the preparation ofmedicinal vehicles, of sutures, of ligatures or of prostheses oralternatively of surgical adhesives.

If, in certain applications, the use of polymers of relatively highmass, of the type of those described in Patent Application EP 0,332,530,is advantageous, the employment of monomers or of oligomers carryingreactive or polymerizable functions (prepolymers) is preferable forother uses. This is the case, in particular, in restorative surgery(bone filler, surgical cements, biological adhesives, and the like) orin dental surgery (dental cements, and the like). In these applications,it is advantageous for the monomer or prepolymer to be able to diffusevery easily into the tissue to be repaired and thus to penetrate intoall the cavities. Polymerization can then take place "in situ" and giverise to an intermeshing of polymer chains having the desired filling,cohesive or adhesive properties.

In this state of the art, one of the essential objectives of theinvention is to provide organic synthetic products which can, inparticular, be used as the basis for the preparation of non-toxic,biocompatible and biofunctional biomaterials which are useful, interalia, as systems for the controlled release of active principles,sutures, ligatures, surgical adhesives or alternatively as surgicalprostheses or implants.

Another essential objective of the invention is to provide organicsynthetic products which are in the form of prepolymers and/or ofmonomers capable of easily diffusing into biological tissues and ofpolymerizing in situ, indeed in vivo, to satisfactorily provide for thefunctions of filling, of reinforcing cohesion or of adhesion.

STATEMENT OF THE INVENTION

These objectives and others are achieved by the present invention whichrelates, in the first place, to a novel organic product containing atleast two thiol or derived functions and/or carboxyl functions, whichmay or may not be protected, and/or carbonyl functions, of followinggeneral formula: ##STR2## in which: R is a hydrocarbon chain, preferablyan alkyl chain containing from 1 to 50 carbon atoms and, morepreferentially still, an aliphatic chain having from 1 to 10 carbonatoms,

R₁ and R₂ are identical or different and are chosen from the followinggroups: ##STR3## R₃, R₄, R₅, R₆ and R₇ independently represent hydrogenor an aliphatic and/or alicyclic and/or aromatic group, preferably alower alkyl group and/or an aromatic group and, more preferentiallystill, one of the following groups: ##STR4## x, y and z=1 or 2, with theexception of the products of formula (I) in which:

R=--(CH₂)_(t) with t=2, 4 or 6 to 12,

R₁ and R₂ are identical and correspond to OH, --O-alkyl, --NH₂ or--N-alkyl,

R₃ and R₄ are identical and represent hydrogen, --CH₃ or --CH₂ --COOH,

x and y are identical and are equal to 1 or 2.

For reasons of simplification, the aromatic rings are denoted by Phethroughout the present statement.

Within the meaning of the present invention, the term "lower alkyl"denotes radicals comprising from 1 to 6 carbon atoms.

BETTER WAY OF PRODUCING THE INVENTION

The biological compounds corresponding to this formula advantageouslyhave a relatively low molecular mass (less than 2 000) and can thereforerapidly and easily diffuse through the networks of proteins (collagen,elastin, and the like) or glycoproteins of which tissues are composed.This is a property which it is advantageous to exploit in the field ofadhesives.

A first subgroup of the products of the invention comprises those inwhich the R₁ and R₂ radicals represent OR₅.

More precisely still, as soon as R₃ and R₄ correspond to hydrogen, thereis present an oligomer having, at each of its two ends, an SH functioncarded by a cysteine or derived unit ("di-SH" oligomer).

These SH functions have the property of being able to react with eachother, to form disulfide bridges and to make it possible to obtain longchains. This property can be exploited in order to prepare biodegradableyarns, films or viscous solutions.

The presence of carboxyl functions on these di-SH compounds makes itpossible to envisage interactions with other molecules (for examplenatural macromolecules). This tends to improve the adhesive properties.In addition, these carboxyl functions bring about a hydrophilic natureand an ability to attach active principles.

A second typical subgroup of the products in accordance with theinvention combine the products corresponding to the abovementionedgeneral formula, in which the R₁ radical represents: ##STR5## and R₂represents --O--R₅, or vice versa.

As soon as R₅ and R₆ consist of hydrogen, these compounds may bedescribed as "tri-SH" oligomers. These oligomers, the SH ends of whichare capable of reacting in order to form disulfide bridges, allowpossibilities of the development of multidirectional networks to beanticipated, which networks can only improve the mechanical properties,the adhesive powers and the resistance to biodegradation of the productsaccording to the invention.

A third subgroup of organic products according to the invention consistsof the products in which the R₁ and R₂ radicals consist of the radical:##STR6##

With R₃, R₄ and R₆ corresponding to hydrogen, a tetrafunctional oligomeris defined which contains four SH units at its ends ("tetra-SH"oligomer). This multiplicity of potential anchoring points canadvantageously be exploited in the field of biomaterials. This comeswithin the continuation of that which was shown above for the di- andtrifunctional oligomers.

The cysteine unit used can be formed by cysteine itself: x, y and z=1,or by homocysteine: x, y, z=2, which can optionally result from cystineor homocystine.

The alkyl chain R, which is optionally substituted, defines the radical:##STR7## in the formula (I), so that it belongs to the group of residuesof poly-, advantageously di-, carboxylic acids, with the exception ofcitric acid, R preferably being selected from the following groups:##STR8## with: p≦5, preferably equal to 2 (succinic acid) or to 3(glutaric acid),

q≦5, preferably equal to 1 (aspartic acid) or to 2 (glutamic acid),

and, finally, r≦5, preferably equal to 1 (malic acid).

R can also be composed of low molecular mass polylactic and/orpolyglycolic and/or poly(amino acid) chains.

These oligomers in accordance with the invention are carriers of SHfunctions which confer on them abilities to polymerize and/or tocrosslink, optionally in the presence of an oxidizing agent. Theytherefore make it possible to obtain, after oxidation, polymers, whichmay or may not be crosslinked, which can be used as biomaterials andwhich are optionally degradable to natural metabolites, i.e. which areinvolved in the biological cycles of mammals.

Moreover, their size and their structure are such that they can easilymigrate and penetrate into biological tissues.

It follows that these oligomers can without difficulty reach thetargeted biological sites and can polymerize "in situ" so as to form anintermeshing and/or a network of polymer chains.

These oligomers therefore find outlets as constituents of products forrestorative surgery (bone filler, surgical cements, biologicaladhesives, and the like) or for dental surgery (dental cements, and thelike) where their filling, reinforcing of cohesion or adhesiveproperties are exploited.

These properties can also be of advantage in another field ofapplication which is that of the bioadhesive forms used in certainsystems for the controlled release of therapeutic active principles. Incertain applications, it is preferable to employ a liquid form, becausethis facilitates the application of the active principle/prepolymerunit, and then the formation of a polymer matrix in situ in contact withthe mucous membrane (in the presence or in the absence of an oxidizingagent which triggers polymerization) makes possible the controlledrelease of the active principle. Such systems are particularlyadvantageous in the treatment of local complaints.

Moreover, polymerization of the products according to the invention byoxidation of the SH groups to disulfide bridges can also be carried outin vitro and thus can make possible the formation of moldable films orobjects which can be used as biomaterials.

The present invention also relates to polymers capable of being obtainedfrom the oligomers, as described above, and which correspond to thefollowing general formula: ##STR9## in which: R₁ and R₂ are identical ordifferent and are chosen from the following groups: ##STR10## with R₅,R₆ and R₇ independently representing hydrogen or an aliphatic and/oralicyclic and/or aromatic group, preferably a lower alkyl group and/oran aromatic group and, more preferentially still, one of the followinggroups: ##STR11## R is chosen so that the radical: ##STR12## of theformula (I) is a radical belonging to the group of poly-, advantageouslydi-, carboxylic acids, with the exception of citric acid, R preferablybeing selected from the following groups: ##STR13## with: p≦5,preferably equal to 2 or 3,

q≦5, preferably equal to 1 or 2,

and r≦5, preferably equal to 1,

n being between 1 and 100, preferably between 2 and 50 and, morepreferentially still, between 4 and 30,

and x and y corresponding to 1 or 2, as above.

R can also be composed of low molecular mass polylactic and/orpolyglycolic and/or poly(amino acid) chains.

These polymers are polysulfides in which the repeat unit preferablyresults from the combination of succinic acid and of cysteine.

These polymers can be used as the basis for preparing other novelproducts in accordance with the invention which consist of networks(III). This crosslinking is carried out, for example, by amidationand/or esterification, using at least one bridging agent, preferablychosen from polyols and/or polyamides and, more preferentially still,from the following products: cystine, lysine, cystamine and theirderivatives, aldoses and ketoses and their hydrogenated derivatives andother polyols (glycerol).

The invention relates, as novel products, to the networks IIIcrosslinked by bridges resulting from at least one bridging agent of thetype of that mentioned above.

Given that all the products in accordance with the invention describedabove can be fitted into the same preparation sequence, it is clear thatthe present invention also relates to any composition composed of amixture of at least two of the abovesaid products.

The products according to the invention are biocompatible and haveproved to be particularly appropriate for taking part in the compositionof biomaterials.

Another subject of the present invention is thus any material formed bya mixture and/or by a formulation of at least one of the oligomers (I)and/or polymers (II) and/or networks (III) and/or compositions describedabove with biological macromolecules or biodegradable synthetic ornatural polymers, such as:

polysaccharides; e.g. starch, cellulose, chitosan, dextran ormucopolysaccharides, such as hyaluronic acid or chondroitin sulfate;

proteins; e.g. collagen, gelatin, albumins or globulins;

poly(amino acid)s;

polyesters (in particular lactic and/or glycolic polyesters),polyorthoesters, polyanhydrides or polyphosphazenes;

and lipids and phospholipids.

The preparation of the products I, II and III according to the inventionfits into a reaction scheme in which the first stage is the preparationof polymers, including in particular those corresponding to the formulaII, which then give access to the products I, which themselves can bereconverted to polymers II or to networks III.

According to a preferred embodiment of the invention, this preparationconsists in carrying out:

a) a polycondensation between:

on the one hand, a reactant of formula A: ##STR14## with X and Y, whichare identical or different, representing a halogen, preferably chlorine,or an --OR₈ radical, in which R₈ corresponds to hydrogen or to analicyclic or aliphatic radical, preferably chosen from the list of thefollowing radicals: ##STR15## and with an R radical which is ahydrocarbon chain, preferably an alkyl chain, containing from 1 to 50carbon atoms and, more preferably still, an aliphatic chain having from1 to 10 carbon atoms,

and, on the other hand, a reactant of formula B: ##STR16## with R₁ andR₂ corresponding to a definition identical to that given above,

with R₉ and R₁₀, which are identical or different, chosen from thefollowing radicals: H or aliphatic, preferably alkyl, hydrogenadditionally being that which is more preferentially retained, and withx and y classically being equal to 1 or 2,

b) a reduction of the polymer obtained, which may or may not besubsequently converted.

In practice, it is preferable for the compound of formula A to be in theform of an acid halide, for example an acid chloride, and for thecompound B of cysteine nature to be esterified with R₁ and R₂ alkylradicals preferably consisting of methyl radicals.

Two polycondensation techniques can be envisaged for producing polymers,including those of formula II: solution polycondensation or interfacialpolycondensation.

These techniques will be viewed in detail in the examples below.

Once the polymer has been obtained, it is advantageous to hydrolyze theester functions carded by this polymer. This hydrolysis is carried outin water, in mild alkaline medium, in order to conserve the functionsother than the ester functions of the polymer (saponification).

According to a first alternative form of the process in accordance withthe invention, the polymer, which may or may not have been subjected tohydrolysis of its ester functions, is subjected to a reduction b) of thedisulfide bridges which it contains, which makes it possible to obtainmostly difunctional oligomers carrying an SH unit at each of their ends.

The reduction techniques used are conventional. They may be, forexample, those described in Methods in Enzymology, vol. 143, "Sulfur andsulfur amino-acids", W. B. Jakoby and O. W. Griffith, Academic PressInc., Orlando, (1987).

According to a second alternative form of the process according to theinvention, the partially or completely saponified polymer is subjectedto crosslinking. This polymer can be the polycondensate as is or thepolycondensate reduced in accordance with the first alternative form ofthe process according to the invention, which corresponds to the di-SHdifunctional oligomers. The crosslinking takes place via at least onebridging agent and, preferably, in the presence of a coupling agent.

The bridging agent is, preferably, a diol or a diamine having at leastone --S--S-- bond, such as, for example, cystinc dialkyl esther[sic](methyl or ethyl).

The coupling agent is advantageously chosen from the list of followingcompounds: ethyl(diaminopropyl)carbodiimide (EDC) or carbonyldiimidazole(CDI).

It is possible to change the degree of crosslinking by varying theamount of bridging agent used, with respect to the number of acidfunctions of the polymer.

The concentration of bridging agent is defined by the following ratio:

According to the invention, this ratio is between 0.01 and 1. ##EQU1##

The networks III obtained can be symbolized as follows: ##STR17## withZ=O or NH.

--Z--P--Z-- is a bridge deriving from the polyols (Z=0[sic]): HO--P--OHor from the polyamides (Z=NH): H₂ N--P--NH₂.

The reduction of such a network can be carded out in suspension in waterin the presence of dithiothreitol or of tributylphosphine. It results ina mixture of molecules containing a number of-SH functions which can beisolated, lyophilized and stored under nitrogen at a temperature below0° C. It is then possible, under mild oxidation conditions, to reformthe disulfide bridges in order to obtain a network similar to (iiI).

In the specific case where the bridging agent is chosen from thefollowing products: cystamine or esters of cystine or of homocystine,the groups P of the network (III) also contain disulfide bridges and thereduction of the network then results in a mixture mostly composed ofthe di-, tri- and tetra-SH molecules described above (formula I).

The last stage of the process in accordance with the invention, commonto both the alternative forms mentioned above, consists in oxidizing theSH oligomers obtained in the preceding stage, so as to produce polymers,including in particular those of formula (II), and/or networks (III),disulfide bridges being (re)formed.

This oxidation is carried out either, and preferably, in the presence ofat least one oxidizing system comprising, for example, iodine and/or itsderivatives and/or hydrogen peroxide, or by electrochemistry or directlyin air.

The present invention is also targeted at any composition formed by amixture of at least two products of formula I and/or II and/or III.

In particular, the advantageous compositions are those comprisingmixtures of oligomers I because, once reoxidized, the latter result inmulti-SH coatings, gels or biomaterials described above. Thesereoxidized compounds must exhibit a number of mechanical properties, incorrespondence with their characteristics of use. The level of themechanical properties is essentially dependent on the structure of thenetwork formed and on the control of the crosslinking of themultifunctions, preferably multi-SH functions, of the oligomers. Intheory, any multi-SH composition with a mean SH functionality strictlygreater than 2 can give an insoluble network. The mean SH functionalitymay be defined as follows: ##EQU2## with: A=1. number of mono-SHmolecules +2. number of di-SH molecules +3. number of tri-SH molecules+4. number tetra-SH molecules,

B=number of mono-SH molecules+number of di-SH molecules+number of tri-SHmolecules+number of tetra-SH molecules.

Taking into account the possibility of intramolecular reactions whichdisturb the formation of the network by consuming potential nodes, it ispreferable to target F_(mean) values for the mixtures of oligomers ofthe order of 2.1 to 2.5, in order to ensure formation of the network.Generally, the elasticity and the swelling (gel appearance) of thenetwork decreases when the F_(mean) increases.

A desired mean functionality (for example 2.3) can be obtained directlyor indirectly.

According to the direct method, the crosslinking is carried out oflinear polycondensates of known length, in order to estimate therelative proportion of mono-SH with respect to the di-SH units, with asuitable amount of bridging agent, such as cystinc dimethyl ester. Afterreduction of the network obtained, there is available a mixture ofmono-, di-, tri- and tetra-SH in which the F_(mean) will be close tothat desired. It is necessary, however, to make sure of the totalreactivity of the bridging agent and of the totality of the reduction ofthe SS bridges.

The indirect method consists in "overcrosslinking" a linear polymer bytargeting a theoretical F_(mean), in the region of 3 for example, inreducing this network, in determining by quantitative determination theFrocan obtained, in preparing, by reduction of a linear polycondensate,the mixture of mono- and of di- SH close to 2 and in obtaining, bymixing the two quantitatively determined compositions in desiredproportions, in order to obtain [sic] the F_(mean) corresponding to anoptimum for the desired properties.

For applications of biomaterials requiring formation of a gel, itappears desirable to start from a composition, i.e. from a mixture ofoligomers, having an F_(mean) greater than or equal to 2, preferablyless than or equal to 2.6 and, more preferentially still, less or equalto 2.3.

For harder items, filler cements, osteosynthesis components or rigidimplants, it appears desirable to target F_(mean) values greater than orequal to 2.3 and, preferentially, greater than or equal to 2.5.

The oligomers (I), polymers (II) inter alia or networks (III), which mayor may not be functionalized, in accordance with the invention arecompounds exhibiting no direct or indirect toxicity: they are notcarcinogenic, teratogenic, immunogenic or mutagenic. Moreover, they areentirely biodegradable, that is to say that they consist of productswhich fit perfectly well into the metabolic routes (Krebs cycle inparticular) of the human being or animal. The degradation products ofthese compounds are ipso facto fully tolerated.

POSSIBILITY OF INDUSTRIAL APPLICATION

The products in accordance with the invention find advantageousapplications as a biomaterial, which can, for example, be used as thebasis for the manufacture of sutures, of ligatures, of vascular,osseous, tissue or ligamentous surgical prostheses, of implants of anynature or alternatively of a system for the controlled release of activeprinciples.

In particular, it is advantageous to note that the oligomers (I)according to the invention have a low molar mass (less than 1000 Da) andthat they are thus capable of diffusing within biological tissues inorder subsequently to be polymerized and/or crosslinked therein. Theintermeshings which they then form with the glycoproteins provide asolid adhesive bond.

In the reduced form and in combination with an oxidizing system, theseproducts and/or their mixtures are highly suitable as constituents ofsurgical or dental cements, of filler agents or of biological adhesives.These constituents come within the scope of the invention.

In the oxidized form, these constituents are cohesive networks withscattered disulfide bridges having between them adjustable mechanicaland biological properties.

The following Examples 1 to 10 are an illustration of the properties andof the alternative structural forms of the products according to theinvention. They also describe the structures and the methods ofpreparation of the products according to the invention.

EXAMPLES Example 1

Synthesis of the Polymer (1) by Solution Polycondensation inDimethylacetamide (DMAC) of Cystine Dimethyl Ester Hydrochloride and ofSuccinyl Chloride. ##STR18## 25 g (0.073 mol) of cystine dimethyl esterhydrochloride and 400 ml of DMAC are placed in a 1 l reactor. 41.2 ml oftriethylamine (0.293 mol) are then added. 8.1 ml of freshly distilledsuccinyl chloride are diluted in 100 ml of DMAC and the combination isadded to the reaction mixture using a dropping funnel. The reactionmixture is then stirred for 24 hours at room temperature. Theprecipitated triethylammonium salt is removed by filtration and thereaction mixture is then precipitated from 5 l of water. The polymer isrecovered by filtration and dried in an oven under vacuum: 13 g of awhite (slightly pink) powder are thus obtained. The ¹ H NMR (indeuterated trifluoroacetic acid (TFA) [sic] and IR spectra are inagreement. The molar masses, determined by steric exclusionchromatography (SEC) in DMAC and expressed in polystyrene equivalentsare as follows:

    M.sub.n =6200, M.sub.w =9600

Example 2

Synthesis of the Polymer (1) by Water/Toluene InterfacialPolycondensation of Cystine Dimethyl Ester Hydrochloride and of SuccinylChloride.

25 g (0.073 mol) of cystinc dimethyl ester hydrochloride and 200 ml ofDMAC are placed in a 1 l reactor. 31.06 g of anhydrous sodium carbonate(0.293 mol) are then added. A preemulsion is then formed by addition of100 ml of toluene. 8,1 ml of freshly distilled succinyl chloride arethen diluted in 100 ml of toluene and the combination is added to thereaction mixture using a dropping funnel. The reaction mixture is thenstirred for 4 hours at room temperature. The polymer, precipitatedduring the reaction, is recovered by filtration and washed with acetoneand then with water. It is dried in an oven under vacuum: 14 g of awhite (slightly pink) powder are thus obtained. The ¹ H NMR (in TFA) andIR spectra are in agreement and similar to those obtained for thepolymer of Example 1. The molar masses, determined by SEC in DMAC andexpressed in polystyrene equivalents, are as follows:

    M.sub.n =5700, M.sub.w =11,500

Example 3

Hydrolysis of the Ester Functions of the Polymer (1): Preparation of thePolymer (2). ##STR19##

5 g of polymer (1) obtained by solution or interfacial polycondensationare suspended in 1 l of water. The pH is adjusted to 10.5 with 1M sodiumhydroxide and maintained at this value throughout the hydrolysis. Theaddition of sodium hydroxide is halted when the solution has becomeclear. The solution is then acidified to a pH<3 by an acid ion exchangeresin. It is concentrated, frozen and then lyophilized. 4.6 g of whitepowder are obtained. The ¹ H NMR (in TFA and in D₂ O) and IR spectra arein agreement and show that all the ester functions are hydrolyzed.

Example 4

Reduction of the Polymer (2) by Dithiothreitol Preparation of theMolecule (3). ##STR20##

3 g of polymer (2) and 2.87 g of dithiothreitol (DTT) are dissolved in70 ml of water under a nitrogen atmosphere. The pH is adjusted to 8.5 byaddition of 1M sodium hydroxide and the solution is stirred for 3 hourswhile bubbling nitrogen through. The mixture is then extracted twicewith 100 ml of ethyl acetate. The aqueous phase is then acidified by anacid ion exchange resin to pH=4.5 and then concentrated and precipitatedfrom an excess of acetone. The sticky precipitate obtained isredissolved in the minimum amount of water and reprecipitated fromacetone. It is finally redissolved in water and lyophilized. 2 g of aslightly yellow product are recovered. The ¹ H NMR spectrum (in D₂ O)obtained is in accordance with the formula (3), the carboxyl groupsbeing in the ionized form.

Example 5

Reduction of the Polymer (2) by Tri-(N- Butyl) Phosphine [sic]:Preparation of the Molecule (3).

2.4 g of polymer (2) are dissolved in 30 ml of water under a nitrogenatmosphere. 120 ml of methanol, degassed beforehand, are then added. 2mlof tri(n-butyl)phosphine are then injected into the reaction mixture.After reacting for 3 hours, the methanol is evaporated using a rotaryevaporator. 50 ml of water are added to the residual aqueous solutionwhich is then extracted twice with 200 ml of ethyl acetate. The aqueoussolution is then acidified and precipitated from acetone, as describedin Example 4. The ¹ H NMR spectrum in D₂ O is identical to that of theproduct obtained in Example 4.

Example 6

Crosslinking of the Polymer (2) by Cystine Dimethyl Ester.

5 g of the polymer (2) and 5.3 g of cystine dimethyl ester hydrochlorideare dissolved in 100 ml of water. 6 g ofN-dimethylaminopropyl-N'-ethylcarbodiimide (EDC) are then dissolved in 5ml of water and immediately added to the reaction mixture. The mixtureimmediately takes on a dark red coloring and then, after a few seconds,a pink precipitate is formed. The reaction is halted after 3 hours and200 ml of water are added. The precipitate is recovered by filtration,washed a number of times with water and then dried in an oven undervacuum.

Example 7

Crosslinking of the Polymer (2) by Cystine Diethyl Ester.

5 g of the polymer (2) and 5.73 g of cystine diethyl ester hydrochlorideare dissolved in 100 ml of water. 6 g ofN-dimethylaminopropyl-N'-ethylcarbodiimide (EDC) are then dissolved in 5ml of water and immediately added to the reaction mixture. The reactionis halted after 3 hours and 200 ml of water are added. The precipitateis recovered by filtration, washed a number of times with water and thendried in an oven under vacuum.

Example 8

Reduction by Dithiothreitol of the Crosslinked Polymer From Example 6.

1 g of the crosslinked polymer from Example 7 and 1.1 g ofdithiothreitol are dissolved in 50 ml of water purged beforehand by astream of nitrogen. The pH is adjusted to 9.5 with 1M sodium hydroxide.The reaction mixture becomes clear and the reaction is halted after 1hour. After six extractions with 50 ml of ethyl acetate, the aqueoussolution is acidified to pH=5 by an exchange resin, reextracted with twotimes 50 ml of ethyl acetate and then lyophilized. The product obtainedis a mixture mainly comprising the following molecules (3), (4) and (5):##STR21## The carboxyl functions are in the ionized form (--COO⁻ Na⁺).The mixture is no longer completely soluble in water when the pH is <3.

Example 9

Reduction by Dithiothreitol of the Crosslinked Polymer From Example6-Hydrolysis of the Ester Functions of the Product Obtained.

The reaction is carried out as described in Example 8, but the reducedsolution is maintained at pH=9.5 for 24 hours at 35° C. After sixextractions with 50 ml of ethyl acetate, the aqueous solution isacidified to pH=5 by an exchange resin, reextracted with two times 50 mlof ethyl acetate and then lyophilized. The product obtained is a mixturemainly comprising the following molecules (3), (6) and (7): ##STR22##

The carboxyl functions are in the ionized form (--COO⁻ Na⁺). The mixturecan be acidified (to pH=2.5) by passing through an ion exchange resin.In this case, the solubility in water is retained.

Example 10

Reduction by Dithiothreitol of the Crosslinked Polymer From Example 7.

1 g of the crosslinked polymer from Example 7 and 1.1 g ofdithiothreitol are dissolved in 50 ml of water purged beforehand by astream of nitrogen. The pH is adjusted to 9.5 with 1M sodium hydroxide.The reaction mixture becomes clear and the reaction is halted after onehour. After six extractions with 50 ml of ethyl acetate, the aqueoussolution is acidified to pH=4 with a 1N HCl solution. A sticky, slightlybrown, precipitate is obtained. It is a mixture mainly composed of thefollowing molecules (3), (8) and (9): ##STR23##

We claim:
 1. Organic product containing at least two thiol or derivedfunctions or carbonyl functions, said organic product having thefollowing general formula:in which: R is a hydrocarbon chain, R₁ and R₂are identical or different and are chosen from the following groups:##STR24## R₃, R₄, R₅, R₆ and R₇ independently represent hydrogen or analiphatic group, an alicyclic group or an aromatic group,x,y and z=1 or2,with the exception of the products of formula (I) in which:R═--(CH₂)_(t) with T=2, 4 or 6 to 12, R₁ and R₂ are identical andcorrespond to OH, --O--alkyl, --NH₂ or --N--alkyl, R₃ and R₄ areidentical and represent hydrogen, --CH₃ or --CH₂ --COOH, x and y areidentical and are equal to 1 or
 2. 2. Product according to claim 1,characterized in that R is an alkyl chain having from 1 to 50 carbonatoms.
 3. Product according to claim 1, characterized in that R is analiphatic chain having from 1 to 10 carbon atoms.
 4. Product accordingto claim 1, characterized in that R₃, R₄, R₅, R₆ and R₇ independentlyrepresent a hydrogen, a lower alkyl group or an aromatic group. 5.Product according to claim 1, characterized in that R₃, R₄, R₅, R₆ andR₇ independently represent a hydrogen or a group selected from thefollowing:--CH₃ ; --CH₂ CH₃ ; --CH₂ --Phe; and ##STR25##
 6. Productaccording to claim 1, characterized in that R₁ and R₂ represent --O--R₅.7. Product according to claim 1, characterized in that R₁ represents:##STR26## and R₂ represents --O--R₅, or vice versa.
 8. Product accordingto claim 1, characterized in that R₁ and R₂ consist of the radical:##STR27##
 9. Product according to claim 1, characterized in that it isconvertible into a polymer by oxidation.
 10. Product according to claim1, characterized in that R is chosen so that the radical: ##STR28## ofthe formula (I) is a radical belonging to the group of the residues ofpoly-carboxylic acids, with the exception of citric acid.
 11. Productaccording to claim 10, characterized in that the radical ##STR29## ofthe formula (I) is a radical belonging to the group of the residues ofdi-carboxylic acids.
 12. Product according to claim 10, characterized inthat R is selected from the group consisting of: ##STR30## with p≦5, q≦5and r≦5.
 13. Product according to claim 11, characterized in that R isselected from the group consisting of: ##STR31## with p≦5, q≦5and r≦5.14. Product according to claim 12, characterized in that p=3, q=1 or 2and r=1.
 15. Product according to claim 13, characterized in that p=3,q=1 or 2 and r=1.
 16. Product according to claim 1, characterized inthat R is composed of low molecular mass chains selected from the groupconsisting of polylactic, polyglycolic and poly(amino acid) chains. 17.Polymers obtained from the product according to claim 10, of thefollowing general formula: ##STR32## wherein n is between 1 and
 100. 18.Polymers obtained from the product according to claim 16, of thefollowing general formula: ##STR33## wherein n is between 1 and
 100. 19.Polymers according to claim 17, characterized in that R₁ and R₂represent --O--R₅.
 20. Polymers according to claim 17, characterized inthat R₁ represents: ##STR34## and R₂ represents --O--R₅, or vice versa.21. Polymers according to claim 17, characterized in that R₁ and R₂consist of the radical: ##STR35##
 22. Networks, characterized in thatthey are composed of polymers according to claim 17 crosslinked bybridges resulting from at least one bridging agent.
 23. Networksaccording to claim 22, characterized in that the bridging agent isselected from the group consisting of polyols and polyamines. 24.Networks according to claim 23, characterized in that the bridging agentis selected from the group consisting of cystinc, cystinc derivatives,lysine, lysine derivatives, aldoses, ketoses, hydrogenated derivativesof aldoses, hydrogenated derivatives of ketoses and polyols. 25.Networks according to claim 24, characterized in that the bridging agentis glycerol.
 26. A composition comprising a mixture of at least two ofthe products according to claim
 1. 27. The composition according toclaim 26, comprising a mixture of oligomers of formula (I), and havingan F_(mean) greater than or equal to
 2. 28. Process for the preparationof a product according to claim 1, comprising the following steps:(a)performing a polycondensation reaction between:a reactant of formula A:##STR36## with X and Y, which are identical or different, representing ahalogen, or an --OR₈ radical, in which R₈ is selected from the groupconsisting of hydrogen, an aliphatic radical and an alicyclicradical,and with R in accordance with the definition given in claim 1,and a reactant of formula B: ##STR37## with R₁ and R₂ as defined inclaim 1, with R₉ and R₁₀, which are identical or different, chosen fromthe following radicals: H or aliphatic,and with x and y=1 or 2; and (b)performing a reduction of the polymer obtained in step (a).
 29. Processaccording to claim 28, wherein X and Y, which are identical ordifferent, represent a chlorine or an --OR₈ radical.
 30. Processaccording to claim 28, wherein R₉ and R₁₀, which are identical ordifferent, are chosen from H or alkyl.
 31. Process according to claim28, wherein R₉ and R₁₀ are hydrogen.
 32. Process according to claim 28further comprising the step of converting the polymer obtained in step(b).
 33. Process according to claim 28, wherein the ester functions ofthe polymer obtained on conclusion of the stage (a) are hydrolyzed. 34.Process according to claim 28, characterized in that, prior to the stageb), the at least partially saponified polymer is crosslinked, thecrosslinking taking place via at least one bridging agent and,preferably, in the presence of a coupling agent, so as to obtain anetwork.
 35. A process as claimed in claim 34 wherein the network is ofthe type of those according to claim
 22. 36. A process according toclaim 34, wherein R₁ and R₂ are OH.
 37. A process for the preparation ofa polymer of formula (II): ##STR38## wherein: n is between 1 and 100;R₁and R₂ are identical or different and each represents ##STR39## whereinR₅, R₆ and R₇ independently represent hydrogen, and aliphatic group, analicyclic group or an aromatic group; R is chosen so that the radical##STR40## is a residue of a polycarboxylic acid which is not citricacid; and x, y and z are each 1 or 2; in which process a product offormula (I) as claimed in claim 1 is oxidized using an oxidizing system.38. A process for the preparation of a network comprised of polymers offormula (II) as claimed in claim 17, wherein the polymers arecrosslinked by bridges resulting from at least one bridging agent.
 39. Aprocess as claimed in claim 38 wherein the bridging agents are polyolsor polyamines.
 40. A process as claimed in claim 37 wherein theoxidizing system comprises iodine, iodine derivatives, hydrogen peroxideor mixtures thereof.
 41. A biomaterial comprised of novel organicproducts as claimed in claim 1, polymers obtained by oxidizing saidproducts, networks obtained by crosslinking said polymers, or mixturesthereof.
 42. A biomaterial as claimed in claim 41 which furthercomprises biological macromolecules or biodegradable synthetic ornatural polymers.
 43. Product according to claim 9 used as abiomaterial.